In Parkinson's disease STN stimulation enhances responsiveness of movement initiation speed to high reward value

Objective: The subthalamic nucleus (STN) is part of the motor, associative, and limbic cortico-striatal circuits through which it can influence a range of behaviours, with preclinical and clinical evidence suggesting that the STN is involved in motivational modulation of behaviour. In the present study, we investigated if in Parkinson’s disease (PD) motivational modulation of movement speed is altered by deep brain stimulation (DBS) of the STN (STN-DBS). / Methods: We studied the effect of monetary incentive on speed of movement initiation and execution in a computer-based simple reaction time task in 10 operated patients with Parkinson’s disease using a STN DBS ON/OFF design and also in 11 healthy participants. / Results: Prospect of reward improved speed of movement initiation in PD patients both with STN-DBS ON and OFF. However, only with STN-DBS ON, the patients showed greater speeding of initiation time with higher reward magnitude, suggesting enhanced responsivity to higher reward value. Also, on the rewarded trials, PD patients ON stimulation made more anticipation errors than on unrewarded trials, reflecting a propensity to impulsive responses triggered by prospect of reward by subthalamic stimulation. The motivational modulation of movement speed was preserved and enhanced in PD with STN-DBS. / Conclusion: Motivational modulation of movement speed in PD is maintained with STN-DBS, with STN stimulation having a further energizing effect on movement initiation in response to greater incentive value. Our results suggest that STN plays a role in integrating motivational influences into motor action, which may explain some previous reports of STN-DBS induced impulsivity with increased motivational salience of stimuli

The acute effects of dopaminergic medication and deep brain stimulation of subthalamic nucleus on basic executive functions including shifting, updating and inhibition in Parkinson’s disease patients

The general aim of the present PhD thesis is to investigate the effects of two common treatments of Parkinson’s disease (PD), dopamine medication and deep brain stimulation (DBS) of the subthalamic nucleus (STN), on executive functions (EFs) including the abilities of shifting, updating and inhibition in patients relative to age-matched healthy controls. The thesis consisted of four studies. Study 1 examined the acute effect of dopamine medication on PD patients who had been previously diagnosed with impulsive control disorders (ICDs) using a moving dots paradigm to assess their abilities of context monitoring. Study 2 created predictive models using behavioural data from the previous studies to build classification predictive models, to demonstrate that behavioural patterns on a moving dots task could potentially be used as a screening tool in predicting vulnerability to develop ICDs in PD patients. Study 3 examined the acute effects of STN DBS on task switching using a moving dots paradigm in PD patients. Study 4 investigated the acute effects of STN DBS on reprogramming actions when encountering surprising events, using a probabilistic reaction time (RT) task. It was hypothesised that for both treatments, being ON states would induce impaired executive functions that lead to faster RTs and more incorrect responses in PD patients, due to the ‘dopamine overdose hypothesis’ and the DBS interrupting the role of the STN in inhibitory control. In summary, the acute manipulation of both treatments did not render significantly negative effects on PD patients behaviourally. However, PD patients still showed certain difference on task performance compared to age-matched healthy controls, which may shed lights on the role of basal ganglia in basic abilities of EFs. Furthermore, the behavioural patterns on tasks involving core aspects of EFs may potentially be used to predict the onset of ICDs, which provides benefits to clinical purpose

Motor symptoms in Parkinson's disease: A unified framework

Parkinson’s disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (akinesia and bradykinesia, tremor and rigidity), PD patients show additional motor deficits, including: gait disturbance, impaired handwriting, grip force and speech deficits, among others. Some of these motor symptoms (e.g., deficits of gait, speech, and handwriting) have similar clinical profiles, neural substrates, and respond similarly to dopaminergic medication and deep brain stimulation (DBS). Here, we provide an extensive review of the clinical characteristics and neural substrates of each of these motor symptoms, to highlight precisely how PD and its medical and surgical treatments impact motor symptoms. In conclusion, we offer a unified framework for understanding the range of motor symptoms in PD. We argue that various motor symptoms in PD reflect dysfunction of neural structures responsible for action selection, motor sequencing, and coordination and execution of movement

Effects of deep brain stimulation of the subthalamic nucleus and the pedunculopontine nucleus on cognitive function in Parkinson's disease

The general aim of this thesis was to investigate the cognitive effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the pedunclopontine nucleus (PPN) in Parkinson’s disease (PD). In Study 1, acute STN stimulation did not induce impulsivity on a probabilistic decisionmaking task, suggesting STN-DBS induced impulsivity may occur in tasks involving conflict, reward or time pressure. This study has clarified that the inhibitory deficits associated with STN-DBS are situation and task specific, which makes it clear why new cases of post-operative impulse control disorders are only reported in some patients. In Study 2, the STN-DBS induced decline in verbal fluency (VF), greater for semantic than phonemic fluency, was found to be a surgical rather than an acute stimulation effect, mainly due to reduced switching but no change in cluster size. Therefore, future work in identifying the mechanisms of the STN-DBS induced VF decline should focus on surgical rather than stimulation effects. In Study 3, patients failed to benefit from corrective feedback to enhance their learning relative to a trial-and-error version when performing visual conditional associative learning tasks (VCLT) with STN-DBS on versus off. STN-DBS seemed to influence proactive interference resolution on the VCLTs. These results have implications for the use of adjunct interventions such as speech therapy or physiotherapy following STN-DBS surgery. In Study 4, PPN-DBS surgery did not have an impact on most aspects of cognition assessed and the only consistent decline was in switching category VF. For the two patients who developed dementia after PPN-DBS surgery, resuming low frequency stimulation improved working memory and attention. The findings from these studies provide further evidence and clarity regarding the cognitive sequel of STN-DBS and PPN-DBS for PD and confirm that the former can be a good treatment of choice for mid to late-stage Parkinson’s disease without the risk of major cognitive adverse effects

Spectrum of impulse control behaviours in Parkinson's disease: pathophysiology and management.

Impulse control behaviours (ICBs) are a range of behaviours linked by their reward-based, repetitive natures. They can be precipitated in Parkinson's disease (PD) by dopamine replacement therapy, often with detrimental consequences for patients and caregivers. While now a well-recognised non-motor feature of treated PD, much remains unknown about the influence of risk factors, pathophysiological mechanisms, vulnerability factors for specific types of behaviour and the optimal management strategies. Imaging studies have identified structural and functional changes in striatal and prefrontal brain regions, among others. Gene association studies indicate a role for genetic predisposition to PD-ICB. Clinical observational studies have identified potential modifiable and non-modifiable risk factors. Psychological studies shed light on the neurocognitive domains implicated in PD-ICBs and identify psychosocial determinants that may perpetuate the cycle of impulsive and harm-avoidance behaviours. Based on these results, a range of pharmacological and non-pharmacological management strategies have been trialled in PD-ICBs with varying success. The purpose of this review is to update clinicians on the evidence around the pathophysiology of PD-ICB. We aim to translate our findings into an interpretable biopsychosocial model that can be applied to the clinical assessment and management of individual cases of PD-ICB

Computational techniques for optimization of subthalamic nucleus deep brain stimulation in the context of Parkinson's disease

Deep brain stimulation has been successfully used in the treatment of Parkinson’s disease for more than two decades, with deep brain stimulation of the subthalamic nucleus significantly improving motor function. Symptoms of the disease (e.g., tremor, rigidity, bradykinesia) are measured by the Unified Parkinson’s Disease Rating Scale Part III, but uncertainty remains concerning the areas in and around the subthalamic nucleus that are associated with each particular symptoms included in UPDRS-III. Here, we retrospectively examine a cohort of Parkinson’s patients implanted at the Center for Neuromodulation in the Ohio State Wexner Medical Center. By combining anatomically-detailed pre-operative magnetic resonance imaging with post-operative computed tomographic imaging, we accurately determine the actual location of implanted electrode leads, then model a volume of tissue activation around each electrode to estimate the neuronal cell bodies and fiber tracts that are most likely to be affected by the stimulation parameters (i.e., voltage, pulse width, and frequency) that are programmed by clinicians during follow-up. By correlating these volumes of tissue activation with each motor function subscore, we have built three-dimensional statistical and probabilistic maps in and around the subthalamic nucleus that will allow clinicians to target lead placement and stimulation to particular deep brain regions based on patient-specific symptoms.2015 College of Arts and Sciences Undergraduate Research Scholarship (Ohio State University Colleges of Arts & Sciences)2015 Social and Behavioral Sciences Undergraduate Research Grant (Ohio State Department of Social & Behavioral Sciences)2014 University Honors & Scholars Summer Research Fellowship (Ohio State University Honors & Scholars)No embargoAcademic Major: Neuroscienc

Cortical - Basal Ganglia Circuits: Control of Behaviour and Alcohol Misuse

Highly organised and differentiated neural circuits form and unite to link the cortex with the basal ganglia and thalamus to mediate movement, cognition and behaviour. Previous assertions that the basal ganglia primarily acted to filter cortical information to facilitate motor outputs only have since given way to an understanding of the basal ganglia as a relay and gating structure with functionally and structurally segregated inputs, functions and outputs. Thus, cortical – basal ganglia circuits can be segregated into three broadly separable functional domains mediating motor (primary and supplementary motor cortex (SMA) and putamen), cognitive (dorsolateral prefrontal cortex (dlPFC) and caudate), and limbic (ventromedial prefrontal cortex and ventral striatum (VS)) processes. In addition, cognitive and behavioural programs that pass through the cortical – basal ganglia circuitry can be subject to filtering by the subthalamic nucleus (STN), which receives direct projections from the cortex. This work first demonstrated the functional organisation of segregated intrinsic cortical – basal ganglia circuits in humans, alongside a detailed map of functional subzones within STN, a small and technically inaccessible midbrain structure. The behavioural relevance of the defined cortical – basal ganglia circuits was investigated by examining the cognitive constructs of impulsivity and compulsivity. Waiting impulsivity, a tendency towards rapid premature responses that has been associated with compulsive drug use, was associated with connectivity between limbic regions including subgenual anterior cingulate cortex, VS and STN. However, motor impulsivity, in the form of stopping ability, was associated with motoric regions including pre-SMA and STN. Compulsivity was captured as deficits in: reversal learning, implicating lateral orbitofrontal cortex; attentional shifting, implicating dlPFC; and habit learning, implicating SMA. Neural circuit changes were also examined in individuals with alcohol dependence and binge drinkers. Waiting impulsivity was elevated in both groups and the functional connectivity, microstructural integrity and anatomical connectivity of the neural circuit underlying waiting impulsivity were associated with problematic drinking behaviours in both groups. Together, this work establishes that discrete functional subzones of small subcortical regions can be differentiated in humans and that their behavioural correlates can be similarly mapped. The definition of intrinsic network architecture underlying a particular behaviour and the demonstration its disturbance in psychiatric groups will crucially inform the development of future diagnostic and therapeutic models